The RAS/RAF/MEK/ERK pathway is involved in growth factor-mediated proliferative signaling. This pathway comprises an evolutionarily conserved signaling cascade activated by the RAS small guanidine triphosphatase (GTPase), which in turn activates RAF, which in turn phosphorylates and activates MEK, and which in turn activates extracellular signal-regulated kinase (ERK). ERK-mediated phosphorylation of a variety of transcriptional factors regulates several key cellular activities including proliferation, differentiation, migration, survival and angiogenesis.
Aberrant signaling through the RAS/RAF/MEK/ERK pathway leads to unconstrained cell growth and cell transformation and is a characteristic feature of many cancers. Inappropriate activation of the RAS pathway can occur through several distinct mechanisms, including activating mutations in KRAS, activating mutations in NRAS, and the serine/threonine kinase BRAF. Approximately 15% of human cancers carry activating RAS mutations, including colorectal cancer (CRC) (40% KRAS mutations), pancreatic cancer (KRAS 70-90% mutations) and non-small cell lung cancer (NSCLC) (30% KRAS mutations). Activating mutations in BRAF occur in 7-8% of all solid tumors and in 60% of malignant melanomas, 8-15% of CRC and 3% of cases of pancreatic carcinoma. Somatic mutations in BRAF and NRAS occur in 50-60% and 15-20% of cutaneous melanomas respectively. In general, such activating mutations of KRAS, NRAS and BRAF are considered to be critical promoters of malignancy.
Further, insulin-like growth factor-1 receptor (IGF1R), a transmembrane tyrosine kinase, is widely expressed on normal tissues. The receptor is activated by binding of the natural ligands IGF1 and IGF2 and leads to activation of the PI3K/AKT and the RAS/RAF/MEK/ERK pathway. Signaling through the phosphatidylinositol 3′ kinases (PI3K) regulates diverse cellular functions, including protein synthesis and glucose metabolism, cell survival and growth, proliferation, cellular resilience and repair, cell migration, and angiogenesis. Upon activation, PI3K generates PIP3, a lipid “second messenger”, which in turn activates AKT (PKB), a serine/threonine kinase which is probably the best understood downstream effector of PI3K. The PI3K signaling is negatively regulated by action of dual specificity protein phosphatases/3-PI phosphatases, namely the tumor suppressor PTEN.
Activation of the PI3K/AKT pathway associated with increased IGF1R signaling is known to occur in various cancer types, such as pancreatic carcinoma, colorectal cancer and melanoma. IGF1R is often found to be overexpressed by cancer cell lines and human cancers, and many cancer cell lines are mitogenically responsive to physiological concentrations of IGFs. IGF1R overexpression, however, in contrast to other receptor tyrosine kinase receptors, does not appear to be associated with gene amplification or gene mutation. IGF1R is found to establish resistance to epidermal growth factor receptor (EGFR) inhibitors in EGFR amplified tumors by loss of insulin-growth factor binding protein expression.
Many cancers, particularly those carrying EGFR amplifications, KRAS-mutations, or BRAF-mutations are amenable to treatment with epidermal growth factor receptor (EGFR) inhibitors, IGF1R inhibitors and/or BRAF-inhibitors, respectively. However, in many cases these cancers acquire resistance to these chosen therapeutic and ultimately become refractory to treatment.
In spite of numerous treatment options for cancer patients, there remains a need for effective and safe therapeutic agents and a need for their preferential use in combination therapy. In particular, there is a need in the art for novel methods of treating cancers, particularly those carrying EGFR amplification, EGFR activating mutations, IGF1R activating signature (e.g., overexpression of IGF1R, high circulating levels of IGF-1, or high levels of IGFBP1), KRAS-mutant, NRAS-mutant or BRAF-mutated cancers, especially those cancers that have been resistant and/or refractive to current therapies.